Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH02 
Vildagliptin, a member of the islet enhancer class, is a potent and selective DPP-4 inhibitor.

The administration of vildagliptin results in a rapid and complete inhibition of DPP-4 activity, resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).

By increasing the endogenous levels of these incretin hormones, vildagliptin enhances the sensitivity of beta cells to glucose, resulting in improved glucose-dependent insulin secretion. Treatment with vildagliptin 50-100 mg daily in patients with type 2 diabetes significantly improved markers of beta cell function including HOMA-β (Homeostasis Model Assessment–β), proinsulin to insulin ratio and measures of beta cell responsiveness from the frequently-sampled meal tolerance test. In non-diabetic (normal glycemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose levels.

By increasing endogenous GLP-1 levels, vildagliptin also enhances the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion.

The enhanced increase in the insulin/glucagon ratio during hyperglycemia due to increased incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to reduced glycemia.

The known effect of increased GLP-1 levels delaying gastric emptying is not observed with vildagliptin treatment.

Clinical Experience

More than 15,000 patients with type 2 diabetes participated in double-blind placebo- or active- controlled clinical trials of up to more than 2 years treatment duration. In these studies, vildagliptin was administered to more than 9,000 patients at daily doses of 50 mg once daily, 50 mg twice daily or 100 mg once daily. More than 5,000 male and more than 4,000 female patients received vildagliptin 50 mg once daily or 100 mg daily. More than 1,900 patients receiving vildagliptin 50 mg once daily or 100 mg daily were ≥ 65 years of age. In these trials, vildagliptin was administered as monotherapy in drug-naïve patients with type 2 diabetes or in combination in patients not adequately controlled by other antidiabetic medicinal products.

Overall, vildagliptin improved glycemic control when given as monotherapy or when used in combination with metformin, a sulfonylurea, a thiazolidinedione, with insulin, or in triple combination with metformin and a sulfonylurea as measured by clinically relevant reductions in HbA1c from baseline at study endpoint (see Table 7 and below data).

In clinical trials, the magnitude of HbA1c reductions with vildagliptin was greater in patients with higher baseline HbA1c.

GAL API FEB15 CL V11                                           9             REF SmPC 05.14 CDS 30.07.14 In a 52-week double-blind controlled trial, vildagliptin (50 mg twice daily) reduced baseline HbA1c by -1% compared to -1.6% for metformin (titrated to 2 g/day) statistical non-inferiority was not achieved.
Patients treated with vildagliptin reported significantly lower incidences of gastrointestinal adverse reactions versus those treated with metformin.

In a 24-week double-blind controlled trial, vildagliptin (50 mg twice daily) was compared to rosiglitazone (8 mg once daily). Mean reductions were -1.20% with vildagliptin and -1.48% with rosiglitazone in patients with mean baseline HbA1c of 8.7%. Patients receiving rosiglitazone experienced a mean increase in weight (+1.6 kg) while those receiving vildagliptin experienced no weight gain (-0.3 kg). The incidence of peripheral edema was lower in the vildagliptin group than in the rosiglitazone group (2.1% vs. 4.1% respectively).
In a 24 week trial, vildagliptin (50 mg twice daily) was compared to pioglitazone (30 mg once daily) in patients inadequately controlled with metformin (mean daily dose: 2020 mg). Mean reductions from baseline HbA1c of 8.4% were - 0.9% with vildagliptin added to metformin and -1.0% with pioglitazone added to metformin. The decrease in HbA1c from baseline >9.0% was greater (-1.5%) in both treatment groups. A mean weight gain of +1.9 kg was observed in patients receiving pioglitazone added to metformin compared to +0.3 kg in those receiving vildagliptin added to metformin.
In a clinical trial of 2 years' duration, vildagliptin (50 mg twice daily) was compared to glimepiride (up to 6 mg/day – mean dose at 2 years: 4.6 mg) in patients treated with metformin (mean daily dose: 1894 mg). After 1 year mean reductions in HbA1c were -0.4% with vildagliptin added to metformin and - 0.5% with glimepiride added to metformin, from a mean baseline HbA1c of 7.3%. Body weight change with vildagliptin was - 0.2 kg vs + 1.6 kg with glimepiride. The incidence of hypoglycemia was significantly lower in the vildagliptin group (1.7%) than in the glimepiride group (16.2%). At the study endpoint (2 years), the HbA1c was similar to baseline values in both treatment groups and the body weight changes and hypoglycemia differences were maintained.
In a long-term trial of 2 years, vildagliptin (50 mg twice daily) was compared to gliclazide (up to 320 mg/day). After two years, mean reduction in HbA1c was -0.5% for vildagliptin and -0.6% for gliclazide, from mean baseline HbA1c of 8.6%. Statistical non-inferiority was not achieved.
Vildagliptin was associated with fewer hypoglycemic events (0.7%) than gliclazide (1.7%).
In a 52-week trial, vildagliptin (50 mg twice daily) was compared to gliclazide (mean daily dose: 229.5 mg) in patients inadequately controlled with metformin (metformin dose at baseline 1928 mg/day). After 1 year, mean reductions in HbA1c were -0.81% with vildagliptin added to metformin (mean baseline HbA1c 8.4%) and -0.85% with gliclazide added to metformin (mean baseline HbA1c 8.5%); statistical non-inferiority was achieved (95% CI -0.11 – 0.20). Body weight change with vildagliptin was +0.1 kg compared to a weight gain of +1.4 kg with gliclazide.
In a 24-week trial the efficacy of the fixed dose combination of vildagliptin and metformin (gradually titrated to a dose of 50 mg/500 mg twice daily or 50 mg/1000 mg twice daily) as initial therapy in drug-naïve patients was evaluated. Vildagliptin/metformin 50 mg/1000 mg twice daily reduced HbA1c by -1.82%, vildagliptin/metformin 50 mg/500 mg twice daily by -1.61%, metformin 1000 mg twice daily by -1.36% and vildagliptin 50 mg twice daily by -1.09% from a mean baseline HbA1c of 8.6%.
The decrease in HbA1c observed in patients with a baseline ≥ 10.0% was greater.
In a 24-week double blind placebo-controlled trial, vildagliptin (50 mg once daily) reduced HbA1c by -0.74% from a mean baseline of 7.9% in patients with moderate renal impairment and -0.88% from a mean baseline of 7.7% in patients with severe renal impairment. Vildagliptin significantly decreased HbA1c when compared to placebo (reductions in patients with moderate and severe renal impairment in the placebo group were -0.21% and -0.32% respectively, from similar mean baseline values).

A 24-week randomized, double-blind, placebo-controlled trial was conducted in 449 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with a stable dose of basal or premixed insulin (mean daily dose 41 U), with concomitant use of metformin (N = 276) or without concomitant metformin (N = 173). Vildagliptin in combination with insulin significantly decreased HbA1c compared with placebo. In the overall population, the placebo-adjusted mean reduction from a mean baseline HbA1c 8.8% was -0.72%. In the subgroups treated with insulin with or without concomitant metformin the placebo-adjusted mean reduction in HbA1c was -0.63% and - GAL API FEB15 CL V11                                          10             REF SmPC 05.14 CDS 30.07.14 0.84%, respectively. The incidence of hypoglycemia in the overall population was 8.4% and 7.2% in the vildagliptin and placebo groups, respectively. Patients receiving vildagliptin experienced no weight gain (+0.2 kg) while those receiving placebo experienced weight reduction (-0.7kg).

A 24-week randomized, double-blind, placebo-controlled trial was conducted in 318 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with metformin (≥ 1,500 mg daily) and glimepiride (≥4 mg daily). Vildagliptin in combination with metformin and glimepiride significantly decreased HbA1c compared with placebo. The placebo-adjusted mean reduction from a mean baseline HbA1c of 8.8% was -0.76%.
In another 24-week study in patients with more advanced type 2 diabetes not adequately controlled on insulin (short or longer acting, average insulin dose 80 IU/day), the mean reduction in HbA1c when vildagliptin (50 mg twice daily) was added to insulin was statistically significantly greater than with placebo plus insulin (0.5% vs. 0.2%). The incidence of hypoglycaemia was lower in the vildagliptin group than in the placebo group (22.9% vs. 29.6%).


Table 7       Key efficacy results of vildagliptin in placebo-controlled monotherapy trials and in add-on combination therapy trials (primary efficacy ITT population)
Monotherapy placebo                       Mean           Mean change           Placebo- controlled studies                      baseline       from baseline in     corrected mean HbA1c (%)         HbA1c (%) at      change in HbA1c week 24          (%) at week 24
(95%CI)
Study 2301: Vildagliptin 50 mg             8.6               -0.8          -0.5* (-0.8, -0.1) twice daily (N=90)
Study 2384: Vildagliptin 50 mg             8.4               -0.7         -0.7* (-1.1, -0.4) twice daily (N=79)
* p< 0.05 for comparison versus placebo
Add-on / Combination studies
Vildagliptin 50 mg twice daily +           8.4               -0.9          -1.1* (-1.4, -0.8) metformin (N=143)
Vildagliptin 50 mg daily +                 8.5               -0.6          -0.6* (-0.9, -0.4) glimepiride (N=132)
Vildagliptin 50 mg twice daily +           8.7               -1.0          -0.7* (-0.9, -0.4) pioglitazone (N=136)
Vildagliptin 50 mg twice daily +           8.8               -1.0          -0.8* (-1.0, -0.5) metformin + glimepiride (N=152)
* p< 0.05 for comparison versus placebo + comparator

A 52-week multi-center, randomized, double-blind trial was conducted in patients with type 2 diabetes and congestive heart failure (NYHA class I - III) to evaluate the effect of vildagliptin 50 mg bid (N=128) compared to placebo (N=126) on left ventricular ejection fraction (LVEF). Vildagliptin was not associated with a change in left ventricular function or worsening of pre-existing CHF.
Adjudicated cardiovascular events were overall balanced. There were slightly more cardiac events in vildagliptin treated patients with NYHA class III heart failure compared to placebo. However there were imbalances in baseline CV risk favoring placebo and the number of events was low, precluding firm conclusions. Vildagliptin significantly decreased HbA1c compared with placebo (difference of 0.6%) from a mean baseline of 7.8% at week 16. In the subgroup with NYHA class III, the decrease in HbA1c compared to placebo was lower (difference 0.3%) but this conclusion is limited by the small number of patients (n=44). The incidence of hypoglycemia in the overall population was 4.7% and 5.6% in the vildagliptin and placebo groups, respectively.


GAL API FEB15 CL V11                                         11            REF SmPC 05.14 CDS 30.07.14 Cardiovascular risk
A meta-analysis of independently and prospectively adjudicated cardiovascular events from 25 phase III clinical studies of up to more than 2 years duration was performed. It involved 8956 patients with type 2 diabetes treated with vildagliptin and showed that vildagliptin treatment was not associated with an increase in cardiovascular risk. The composite endpoint of adjudicated cardio and cerebrovascular (CCV) events [acute coronary syndrome (ACS, stroke or CCV death], was similar for vildagliptin versus combined active and placebo comparators [Mantel–Haenszel risk ratio 0.84 (95% confidence interval 0.63-1.12)] supporting the cardiovascular safety of vildagliptin. In total, 99 out of 8956 patients reported an event in the vildagliptin group vs 91 out of 6061 patients in the comparator group.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Following oral administration in the fasting state, vildagliptin is rapidly absorbed, with peak plasma concentrations observed at 1.7 hours. Food slightly delays the time to peak plasma concentration to 2.5 hours, but does not alter the overall exposure (AUC). Administration of vildagliptin with food resulted in a decreased Cmax (19%). However, the magnitude of change is not clinically significant, so that Galvus can be given with or without food. The absolute bioavailability is 85%.

Distribution
The plasma protein binding of vildagliptin is low (9.3%) and vildagliptin distributes equally between plasma and red blood cells. The mean volume of distribution of vildagliptin at steady-state after intravenous administration (Vss) is 71 litres, suggesting extravascular distribution.

Biotransformation
Metabolism is the major elimination pathway for vildagliptin in humans, accounting for 69% of the dose. The major metabolite (LAY 151) is pharmacologically inactive and is the hydrolysis product of the cyano moiety, accounting for 57% of the dose, followed by the amide hydrolysis product (4% of dose). In vitro data in human kidney microsomes suggest that the kidney may be one of the major organs contributing to the hydrolysis of vildagliptin to its major inactive metabolite, LAY151. DPP-4 contributes partially to the hydrolysis of vildagliptin based on an in vivo study using DPP-4 deficient rats. Vildagliptin is not metabolized by CYP 450 enzymes to any quantifiable extent. Accordingly, the metabolic clearance of vildagliptin is not anticipated to be affected by co-medications that are CYP 450 inhibitors and/or inducers. In vitro studies demonstrated that vildagliptin does not inhibit/induce
CYP 450 enzymes. Therefore, vildagliptin is not likely to affect metabolic clearance of co-medications metabolized by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4/5.

Elimination
Following oral administration of [14C] vildagliptin, approximately 85% of the dose was excreted into the urine and 15% of the dose is recovered in the feces. Renal excretion of the unchanged vildagliptin accounted for 23% of the dose after oral administration. After intravenous administration to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 and 13 l/h, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The elimination half- life after oral administration is approximately 3 hours.

Linearity / non-linearity
The Cmax for vildagliptin and the area under the plasma concentrations versus time curves (AUC) increased in an approximately dose proportional manner over the therapeutic dose range.

Characteristics in patients
Gender
No clinically relevant differences in the pharmacokinetics of vildagliptin were observed between male and female healthy subjects within a wide range of age and body mass index (BMI). DPP-4 inhibition by vildagliptin is not affected by gender.

Age
GAL API FEB15 CL V11                                          12            REF SmPC 05.14 CDS 30.07.14 In healthy elderly subjects (≥ 70 years), the overall exposure of vildagliptin (100 mg once daily) was increased by 32%, with an 18% increase in peak plasma concentration as compared to young healthy subjects (18-40 years). These changes are, however, not considered to be clinically relevant. DPP-4 inhibition by vildagliptin is not affected by age.

Hepatic impairment
The effect of impaired hepatic function on the pharmacokinetics of vildagliptin was studied in patients with mild, moderate and severe hepatic impairment based on the Child-Pugh scores (ranging from 6 for mild to 12 for severe) in comparison with healthy subjects. The exposures to vildagliptin after a single dose in patients with mild and moderate hepatic impairment was decreased (20% and 8%, respectively), while the exposure to vildagliptin for patients with severe impairment, was increased by 22%. The maximum change (increase or decrease) in the exposure to vildagliptin is ~30%, which is not considered to be clinically relevant. There was no correlation between the severity of the hepatic disease and changes in the exposure to vildagliptin.

Renal impairment

A multiple-dose, open-label trial was conducted to evaluate the pharmacokinetics of the lower therapeutic dose of vildagliptin (50 mg once daily) in patients with varying degrees of chronic renal impairment defined by creatinine clearance (mild: 50 to <80 ml/min, moderate: 30 to <50 ml/min and severe: <30 ml/min) compared to normal healthy control subjects.
Vildagliptin AUC increased on average 1.4, 1.7 and 2-fold in patients with mild, moderate and severe renal impairment, respectively, compared to normal healthy subjects. AUC of the metabolites LAY151 and BQS867 increased on average about 1.5, 3 and 7-fold in patients with mild, moderate and severe renal impairment, respectively. Limited data from patients with end stage renal disease (ESRD) indicate that vildagliptin exposure is similar to that in patients with severe renal impairment.
LAY151 concentrations were approximately 2-3-fold higher than in patients with severe renal impairment.
Vildagliptin was removed by haemodialysis to a limited extent (3% over a 3-4 hour haemodialysis session starting 4 hours post dose).

Ethnic group
Limited data suggest that race does not have any major influence on vildagliptin pharmacokinetics.